Naphthoquinone derivatives as P-glycoprotein inducers in inflammatory bowel disease: 2D monolayers, 3D spheroids, and in vivo models.

Inflammatory bowel disease (IBD) represents a chronic inflammation of the gastrointestinal tract characterized by an overreaction of immune responses and damage at the intestinal mucosal barrier. P-glycoprotein (P-gp) plays a key role to protect the intestinal barrier from xenobiotic accumulation and suppressing excessive immune responses. Therefore, induction/activation of P-gp function could serve as a novel therapeutic target to treat IBD. This study aimed to evaluate the potential therapeutic values of naphthoquinone derivatives (NQ-1 - NQ-8) as P-gp modulators to counterbalance intestinal inflammation. The data indicate that NQ-2, NQ-3, and NQ-4 act as P-gp inducers/activators and are recognized as substrates for P-gp. The three derivatives possess anti-inflammatory effects mediated by suppression of NF-κB and HDAC6 activity in Caco2 monolayer cells. Besides, they reversed LPS-induced intestinal barrier dysfunction by enhancing the expression of P-gp and ZO-1 tight junction proteins in a Caco-2 spheroid model. NQ-2, NQ-3, and NQ-4 showed a robust inhibitory effect on IL-1ß maturation in LPS-primed THP-1 cells. This effect may contribute to alleviate the inflammatory cascades associated with IBD. Distinctively, NQ-2 and NQ-3 exerted anti-NLRP3 inflammasome activity evidenced by the inhibition of CASP-1 activity and the promotion of autophagy. Both compounds induced disruptions of the microtubule network in transfected U2OS-GFP-α-tubulin cells. Treatment with NQ-2 remarkably attenuated dextran sulfate sodium (DSS)-induced colitis in rats by suppressing changes in colon length, colon mass index, and intestinal histopathology scores. Thus, 1,4-naphthoquinone derivatives such as NQ-2 may provide potential therapeutic anti-inflammatory effects for IBD patients and for other NLRP3-associated inflammatory diseases.

Bacteria-Derived Compatible Solutes Ectoine and 5α-Hydroxyectoine Act as Intestinal Barrier Stabilizers to Ameliorate Experimental Inflammatory Bowel Disease.

Earlier studies showed that the compatible solute ectoine (1) given prophylactically before induction of colitis by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats prevented histological changes induced in the colon and the associated rise in inflammatory mediators. This study was therefore conducted to investigate whether ectoine (1) and its 5α-hydroxy derivative (2) would also be effective in treating an already established condition. Two days after inducing colitis in rats by instilling TNBS/alcohol in the colon, animals were treated orally once daily for 1 week with either 1 or 2 (50, 100, 300 mg/kg). Twenty-four hours after the last drug administration rats were sacrificed. Ulcerative lesions and colon mass indices were reduced by 1 and 2 in a bell-shaped manner. Best results were obtained with 100 mg/kg ectoine (1) and 50 mg/kg 5α-hydroxyectoine (2). The solutes normalized the rise in myeloperoxidase, TNFα, and IL-1ß induced by TNBS but did not affect levels of reduced glutathione or ICAM-1, while reducing the level of fecal calprotectin, an established marker for inflammatory bowel disease. The findings indicate that the naturally occurring compatible solutes ectoine (1) and 5α-hydroxyectoine (2) possess an optimum concentration that affords maximal intestinal barrier stabilization and could therefore prove useful for better management of human inflammatory bowel disease.

Mechanisms Involved in the Anti-inflammatory and Vascular Effects of Iberis amara Extract.

The anti-inflammatory potential and vasoprotective effects of an Iberis amara extract in a rat model of arthritis were investigated. I. amara, or bitter candytuft, has long been known for its anti-inflammatory properties on account of its active constituents, including cucurbitacins, kaempferol, and sinapic acid. The present study was intended to explore more in depth its anti-inflammatory activity in both acute (carrageenan rat paw edema) and chronic (adjuvant-induced arthritis) models of inflammation. An extract of I. amara dose-dependently reduced the extent of edema in both models. In the chronic model, this was associated with a reduction in the inflammation mediators tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 and in the antioxidant biomarkers malondialdehyde and total nitrate/nitrite. Because arthritis was reported both clinically and experimentally to contribute towards different vascular complications, it was of interest to study ex vivo the sensitivity of aortic rings in our experimental setup towards norepinephrine, acetylcholine, and sodium nitroprusside. The aortic rings from arthritic rats showed no change in sensitivity to norepinephrine, but showed a reduced sensitivity to sodium nitroprusside and acetylcholine. To show whether the treatment of the arthritis would restore endothelial function, I. amara extract was shown to markedly reduce the reactivity to norepinephrine, but not to appreciably affect the reactivity towards sodium nitroprusside and it had a tendency towards normalizing reactivity to acetylcholine. Taken collectively, the findings imply an improvement in endothelial function and lend support to the use of the extract in rheumatic inflammatory conditions to help safeguard the integrity of the endothelium and reduce the risk of vascular complications.

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in Healthy Male Volunteers.

BACKGROUND AND OBJECTIVE: Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. METHODS: A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞],  half-life (T½) and time to reach Cmax (Tmax) were calculated. RESULTS: The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. CONCLUSION: Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Rice bran extract mitigates depressive-like behavior in dextran sulfate sodium-induced colitis: Involvement of the gut-brain axis and Sirt1 signaling pathway.

Inflammatory bowel disease (IBD) patients frequently suffer from depressive disorders as well. The present study was carried out to explore whether treatment with a standardized rice bran extract (RBE) could affect depression-like behavior in rats with dextran sulfate sodium (DSS)-induced colitis. Male Wistar rats were treated with RBE (100 mg/kg/day; p.o.) for 2 weeks. During the second week, colitis was induced by feeding the rats with 5 % (w/v) DSS in drinking water. RBE protected against DSS-induced body weight loss as well as against the macro- and microscopic inflammatory changes of the colon. Additionally, RBE mitigated DSS-induced dysregulation in blood-brain barrier tight junctional proteins, preserved the hippocampal histopathological architecture and improved the animal behavior in the forced swimming test. This was associated with modulation of hippocampal oxidative stress marker; GSH as well as hippocampal pro-inflammatory mediators; NF-ĸB and IL-1ß. Treatment with RBE also led to a profound increase in the hippocampal levels of Sirt1, PGC-1α, Nrf2, and HO-1, which were drastically dropped by DSS. In conclusion, the study revealed the protective effect of RBE against DSS-induced depressive-like behavior through modulation of different parameters along the gut-brain axis and up-regulated the Sirt1/PGC-1α/Nrf2/HO-1 signaling pathway.

Rice bran extract protects from mitochondrial dysfunction in guinea pig brains.

Mitochondrial dysfunction plays a major role in the development of age-related neurodegenerative diseases and recent evidence suggests that food ingredients can improve mitochondrial function. In the current study we investigated the effects of feeding a stabilized rice bran extract (RBE) on mitochondrial function in the brain of guinea pigs. Key components of the rice bran are oryzanols, tocopherols and tocotrienols, which are supposed to have beneficial effects on mitochondrial function. Concentrations of α-tocotrienol and γ-carboxyethyl hydroxychroman (CEHC) but not γ-tocotrienol were significantly elevated in brains of RBE fed animals and thus may have provided protective properties. Overall respiration and mitochondrial coupling were significantly enhanced in isolated mitochondria, which suggests improved mitochondrial function in brains of RBE fed animals. Cells isolated from brains of RBE fed animals showed significantly higher mitochondrial membrane potential and ATP levels after sodium nitroprusside (SNP) challenge indicating resistance against mitochondrial dysfunction. Experimental evidence indicated increased mitochondrial mass in guinea pig brains, e.g. enhanced citrate synthase activity, increased cardiolipin as well as respiratory chain complex I and II and TIMM levels. In addition levels of Drp1 and fis1 were also increased in brains of guinea pigs fed RBE, indicating enhanced fission events. Thus, RBE represents a potential nutraceutical for the prevention of mitochondrial dysfunction and oxidative stress in brain aging and neurodegenerative diseases.

Catechol conjugates are in vivo metabolites of Salicis cortex.

After oral administration of 100 mg/kg b. w. (235.8 µmol/kg) salicortin to Wistar rats, peak serum concentrations of 1.43 mg/L (13.0 µM) catechol were detected after 0.5 h in addition to salicylic acid by HPLC-DAD after serum processing with ß-glucuronidase and sulphatase. Both metabolites could also be detected in the serum of healthy volunteers following oral administration of a willow bark extract (Salicis cortex, Salix spec., Salicaceae) corresponding to 240 mg of salicin after processing with both enzymes. In humans, the cmax (1.46 mg/L, 13.3 µM) of catechol was reached after 1.2 h. The predominant phase-II metabolite in humans and rats was catechol sulphate, determined by HPLC analysis of serum samples processed with only one kind of enzyme. Without serum processing with glucuronidase and sulphatase, no unconjugated catechol could be detected in human and animal serum samples. As catechol is described as an anti-inflammatory compound, these results may contribute to the elucidation of the mechanism of the action of willow bark extract.

Antidiabetic effects of a standardized Egyptian rice bran extract.

An extract was prepared from Egyptian stabilized rice bran and standardized to contain 2% γ-oryzanol in addition to its content of other bioactives, notably tocotrienol and policosanol. The standardized extract was found to have a concentration-dependent effect on insulin release in vitro, which, however, is not mediated by γ-tocotrienol in rice bran (detected by HPLC) as could have been expected. Policosanol and γ-oryzanol have insulinotropic effects. The in vitro data of rice bran directly translate into in vivo data of rats by using a glucose tolerance test (increase in plasma insulin). Tocotrienols are well known for their apoptotic effect on tumor cells; nevertheless, an attempt was made to study glucose uptake in HEP-G2 cells, which needs to induce an insulin-resistant state by TNF-α. The Egyptian rice bran extract has an antidiabetic effect. γ-Oryzanol, which is a possible precursor of the insulinotropic compound ferulic acid, is a candidate for this effect. Therefore, it is reasonable to assume that the prevalence of diabetes or at least a prediabetic (type 2) situation can be ameliorated by the investigated rice bran extract. The potential usefulness of the extract as a nutraceutical is currently undergoing more thorough investigations.

Niacin modulates depressive-like behavior in experimental colitis through GPR109A-dependent mechanisms.

AIMS: Depression is one of the common neurological comorbidities in patients with inflammatory bowel disease (IBD). The current study aimed to investigate the potential impact of niacin on colitis-induced depressive-like behavior in rats. MATERIALS AND METHODS: Animals were given 5 % dextran sulfate sodium (DSS) in drinking water for one week to induce colitis. Niacin (80 mg/kg), with or without mepenzolate bromide (GPR109A blocker), was administered once per day throughout the experimental period. Rats were tested for behavioral changes using open field and forced swimming tests. KEY FINDINGS: Niacin significantly ameliorated DSS-induced behavioral deficits and alleviated macroscopic and microscopic colonic inflammatory changes. It also augmented the hippocampal levels of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the blood-brain barrier (BBB) integrity. Moreover, niacin decreased hippocampal IL-1ꞵ and NF-ĸB contents but increased GSH, Sirt-1, Nrf-2, HO-1 concentrations. All these beneficial effects were partially abolished by the co-administration of mepenzolate bromide. SIGNIFICANCE: The neuroprotective effect of niacin against DSS-induced depressive-like behavior was partially mediated through GPR109A-mediated mechanisms. Such mechanisms are also involved in modulating neuronal oxidative stress and inflammation via Sirt-1/Nrf-2/HO-1 signaling pathways.

STW 5 is effective in dextran sulfate sodium-induced colitis in rats.

PURPOSE: An herbal preparation, STW 5, used clinically in functional dyspepsia and irritable bowel syndrome, has been shown to possess properties that may render it useful in inflammatory bowel disease (IBD). The present work was conducted to study its effectiveness in a rat model of IBD. METHODS: An experimental model reflecting ulcerative colitis in man was adopted, whereby colitis was induced in Wistar rats by feeding them 5 % dextran sulfate sodium (DSS) in drinking water for one week. STW 5 and sulfasalazine (as a reference standard) were administered orally daily for 1 week before colitis induction and continued during DSS feeding. The animals were then sacrificed, and the severity of colitis was evaluated macroscopically and microscopically. Colon samples were homogenized for determination of reduced glutathione, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-3 as well as myeloperoxidase, glutathione peroxidase, and superoxide dismutase. In addition, colon segments were suspended in an organ bath to test their reactivity towards carbachol, KCl, and trypsin. RESULTS: STW 5 and sulfasalazine were both effective in preventing the shortening of colon length and the increase in both colon mass index and total histology score as well as the changes in biochemical parameters measured except changes in dismutase activity. DSS-induced colitis led to marked depression in colonic responsiveness to the agents tested ex vivo, an effect which was normalized by both drugs. CONCLUSIONS: The findings point to a potential usefulness of STW 5 in the clinical setting of ulcerative colitis.

The herbal preparation STW 5 affects serotonergic pathways in the brain and colon as well as stress parameters in experimental irritable bowel syndrome.

BACKGROUND: Exposure to stress has been related to disturbance in 5-hydroxytryptamine (5-HT) signaling in the brain-gut axis and is considered as a major predisposing factor for the development of irritable bowel syndrome (IBS). The present study aimed to investigate the possible involvement of 5-HT and some other stress-related parameters in the effectiveness of STW 5 against stress-induced IBS. METHODS: Rats were subjected to restraint stress (RS) for 1 h/day for 14 consecutive days to induce IBS-like symptoms and were given STW 5 orally at the same time. At the end of the experiment, blood samples were withdrawn, then animals were euthanized and the brain hippocampi, cerebral cortices, as well as colons were isolated for biochemical and histopathological assessments. RESULTS: RS increased the plasma corticotrophin releasing factor (CRF) with concomitant increase in hippocampal and cortical 5-HT levels, as well as mast cell inflammatory mediators, oxidative stress biomarkers, and histopathological inflammatory changes observed in rat colon. It also decreased the colonic content of 5-HT with consequent decrease in fecal pellet output (FPO). Treatment with STW 5 protected against these changes. CONCLUSION: The protective effect of STW 5 against RS-induced IBS is related to its ability to normalize the induced changes in 5-HT in the brain-gut axis and counteract the stress-induced oxidative stress and inflammation.

Effect of the standard herbal preparation, STW5, treatment on dysbiosis induced by dextran sodium sulfate in experimental colitis.

BACKGROUND: The standardized herbal preparation, STW 5, is effective clinically in functional gastrointestinal disorders and experimentally in ulcerative colitis (UC). The present study explores whether the beneficial effect of STW 5 involves influencing the intestinal microbiota. METHODS: UC was induced in Wistar rats by feeding them 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Rats were treated concurrently with STW 5 and sacrificed 24 h after last drug administration. Fecal samples were used to determine changes in the abundance of selected microbial phyla and genera using real-time PCR. RESULTS: Induction of UC led to dysbiosis and changes in the gut microbiota. The changes included an increase in some genera of the Firmicutes, namely Enterococcus, and a decrease in others, namely Blautia, Clostridium, and Lactobacillus. DSS further induced a marked increase in the abundance of Bacteroidetes and Proteobacteria as well as in the relative abundance of Actinobacteria and its genus Bifidobacterium. Methanobrevibacter levels (phylum Euryarchaeota) were also increased. Microbial dysbiosis was associated with changes in various parameters of colonic inflammation. STW 5 effectively guarded against those changes and significantly affected the indices of edema and inflammation in the UC model. Changes in colon length, colon mass index, inflammatory and apoptotic markers, and histological changes induced by DSS were also prevented. CONCLUSIONS: Dysbiosis plays a contributing role in the development of DSS-induced UC. Derangements in the microbial flora and associated inflammatory processes were largely prevented by STW 5, suggesting that this effect might contribute towards its beneficial usefulness in this condition.

Effect of an herbal preparation, STW 5, in an acute model of reflux oesophagitis in rats.

A multitarget herbal preparation, STW 5, has been used clinically in different gastro-intestinal disorders including functional dyspepsia and irritable bowel syndrome. Previous studies have shown that it possesses properties that may render it useful in gastro-oesophageal reflux disease (GERD). We performed this study to test this compound in an acute model of reflux oesophagitis in rats. Oesophagitis was induced surgically by ligating the pyloric end and fore-stomach. Lower oesophageal pH was measured 3 h later in conscious animals. Five hours after surgery, animals were sacrificed and the oesophagi were examined macroscopically and histologically. Selected markers of inflammation were measured in oesophageal homogenates. STW 5 was given orally for 5 days before induction of oesophagitis. Pantoprazole was used as a reference standard. Ligated animals showed a high incidence of ulcerative lesions associated with a marked increase in myeloperoxidase, thiobarbituric acid-reactive substances, tumor necrosis factor-alpha, and interleukin-1beta. STW 5 did not affect oesophageal pH, but dose-dependently reduced the severity of the oesophageal lesions and normalized the deranged level of the inflammation markers. The beneficial effects were confirmed histopathologically. STW 5 proved to be effective in protecting against inflammatory lesions in this model of oesophagitis, thus warranting further investigation of its potential therapeutic usefulness in GERD.

Micellar solubilization enhances the anti-inflammatory effect of xanthohumol.

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.

Propolis extract protects against radiation-induced intestinal mucositis through anti-apoptotic mechanisms.

Intestinal mucositis is a common side effect during radiotherapy that could be largely prevented by compounds possessing anti-inflammatory or anti-oxidant properties, including extracts of propolis containing a high proportion of flavonoids. A specially formulated aqueous extract of propolis (PWE) has been prepared in such a way to preclude the inclusion of flavonoids but contain mostly organic aromatic acids to study whether it would still protect against radiation-induced intestinal mucositis and to study the possible involvement of apoptotic pathways. Rats were exposed to a gamma radiation dose of 8 Gy from a Cesium-137 source in order to inflict intestinal mucositis. Three days before exposure, rats were given PWE orally and treatment continued for 2 more days. Twenty-four hours later, rats were sacrificed, the small intestine was excised, and sections were examined histologically. Different parameters for apoptosis, inflammation, and oxidative stress were determined in the serum and in intestinal homogenates. Radiation exposure led to histological and biochemical signs of intestinal damage. This was associated with an increase in apoptotic indicators and derangement in oxidative stress parameters. All deranged parameters were largely prevented by PWE. The findings provide evidence that the protective effect of PWE against intestinal radiation damage involves not only its anti-inflammatory and anti-oxidant effects but also its anti-apoptotic properties as well.

Intestinal injury can be effectively prevented by Dunaliella salina in gamma irradiated rats.

Dunaliella salina (D. salina) is one of the most common microalgae that is used as human food. It is isolated from the salty lakes in El-Fayoum and Lake of Bardawil-Sinai in Egypt and can withstand very high concentrations of salt: The potentiality of D. salina, a unicellular biflagellate green alga to protect against intestinal injury induced after radiation exposure was studied. D. salina was given orally in doses of 100 and 200 mg/kg to male Wistar rats for 5 days before exposure to 6 Gray (Gy) gamma radiation and continued for a further two days. Rats were sacrificed 24 h later and intestinal segments were dissected out. One segment was examined histologically and another was used to prepare homogenates to assess relevant biochemical parameters reflecting intestinal injury. Radiation exposure led to a rise in the histological damage score, an increase in tissue tumor necrosis factor (TNF-α), interleukin (IL-1ß) and thiobarbituric acid reactive substances (TBARS) but a reduction in tissue reduced glutathione (GSH) and in serum citrulline. Pretreatment with either dose of D. salina effectively reduced the severity of intestinal mucositis induced by gamma radiation.

STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects. AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole. METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1ß and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2). RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum. CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.

Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis.

OBJECTIVE: Native extracts of curcumin and boswellia are known to exert antiinflammatory properties but have poor bioavailability when given orally. Using advanced micellation technology, it has been possible to produce stable solubilisates of these extracts with markedly enhanced bioavailability. In the present study, we compared the chronic antiinflammatory activities of native and micellar curcumin in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS AND PROCEDURES: Adjuvant arthritis was induced by injecting Freund's complete adjuvant (FCA) into the right hind paw of rats and monitoring paw volume over 3 wk. The drugs were given daily for 3 wk, starting from the day of adjuvant inoculation. The serum was collected at end of the experiment for the assay of inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Solubilized curcumin showed better antiinflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO), and lipid peroxidation markers. The combination of curcumin and boswellia solubilisates synergistically produced an even more potent therapeutic effect. CONCLUSION: The findings confirm that micellar solubilisation of curcumin and boswellia not only increases their bioavailability, but also enhances their biological activity. Micellar curcumin, in particular in combination with micellar boswellia, may thus represent a promising concomitant tool for antiinflammatory treatment and a potential antiinflammatory alternative to synthetic drugs.